Groß Elisabeth, Hilger Ralf-Axel, Schümann Franziska Lea, Bauer Marcus, Bouska Alyssa, Rohde Christian, Willscher Edith, Lützkendorf Jana, Müller Lutz Peter, Edemir Bayram, Mueller Thomas, Herling Marco, Binder Mascha, Wickenhauser Claudia, Iqbal Javeed, Posern Guido, Weber Thomas
Department of Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany.
West German Cancer Center, University Hospital Essen, 45147 Essen, Germany.
Cancers (Basel). 2023 Jun 3;15(11):3043. doi: 10.3390/cancers15113043.
T-cell lymphomas are heterogeneous and rare lymphatic malignancies with unfavorable prognosis. Consequently, new therapeutic strategies are needed. The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and responsible for lysine 27 trimethylation of histone 3. EZH2 is overexpressed in several tumor entities including T-cell neoplasms leading to epigenetic and consecutive oncogenic dysregulation. Thus, pharmacological EZH2 inhibition is a promising target and its clinical evaluation in T-cell lymphomas shows favorable results. We have investigated EZH2 expression in two cohorts of T-cell lymphomas by mRNA-profiling and immunohistochemistry, both revealing overexpression to have a negative impact on patients' prognosis. Furthermore, we have evaluated EZH2 inhibition in a panel of leukemia and lymphoma cell lines with a focus on T-cell lymphomas characterized for canonical EZH2 signaling components. The cell lines were treated with the inhibitors GSK126 or EPZ6438 that inhibit EZH2 specifically by competitive binding at the -adenosylmethionine (SAM) binding site in combination with the common second-line chemotherapeutic oxaliplatin. The change in cytotoxic effects under pharmacological EZH2 inhibition was evaluated revealing a drastic increase in oxaliplatin resistance after 72 h and longer periods of combinational incubation. This outcome was independent of cell type but associated to reduced intracellular platinum. Pharmacological EZH2 inhibition revealed increased expression in SRE binding proteins, SREBP1/2 and ATP binding cassette subfamily G transporters ABCG1/2. The latter are associated with chemotherapy resistance due to increased platinum efflux. Knockdown experiments revealed that this was independent of the EZH2 functional state. The EZH2 inhibition effect on oxaliplatin resistance and efflux was reduced by additional inhibition of the regulated target proteins. In conclusion, pharmacological EZH2 inhibition is not suitable in combination with the common chemotherapeutic oxaliplatin in T-cell lymphomas revealing an EZH2-independent off-target effect.
T细胞淋巴瘤是异质性且罕见的淋巴系统恶性肿瘤，预后不佳。因此，需要新的治疗策略。zeste同源物2增强子（EZH2）是多梳抑制复合物2的催化亚基，负责组蛋白3赖氨酸27三甲基化。EZH2在包括T细胞肿瘤在内的多种肿瘤实体中过表达，导致表观遗传及随后的致癌失调。因此，EZH2的药物抑制是一个有前景的靶点，其在T细胞淋巴瘤中的临床评估显示出良好结果。我们通过mRNA谱分析和免疫组织化学研究了两个T细胞淋巴瘤队列中的EZH2表达，两者均显示过表达对患者预后有负面影响。此外，我们评估了一组白血病和淋巴瘤细胞系中的EZH2抑制情况，重点是具有典型EZH2信号成分特征的T细胞淋巴瘤。用抑制剂GSK126或EPZ6438处理细胞系，这些抑制剂通过在腺苷甲硫氨酸（SAM）结合位点竞争性结合来特异性抑制EZH2，并与常用的二线化疗药物奥沙利铂联合使用。评估了药物性EZH2抑制下细胞毒性作用的变化，结果显示在联合孵育72小时及更长时间后，奥沙利铂耐药性急剧增加。这一结果与细胞类型无关，但与细胞内铂含量降低有关。药物性EZH2抑制显示固醇调节元件结合蛋白SREBP1/2和ATP结合盒转运体亚家族G转运蛋白ABCG1/2的表达增加。后者由于铂流出增加而与化疗耐药相关。敲低实验表明这与EZH2的功能状态无关。对受调控的靶蛋白进行额外抑制可降低EZH2抑制对奥沙利铂耐药性和流出的影响。总之，在T细胞淋巴瘤中，药物性EZH2抑制与常用化疗药物奥沙利铂联合使用并不合适，这显示出一种不依赖EZH2的脱靶效应。
